As used herein, the term "blood-derived compositions" includes whole blood, blood plasma, blood plasma fractions, blood plasma precipitate (e.g., cryoprecipitate, ethanol precipitate or polyethylene glycol precipitate), supernatant (e.g., cryosupernatant, ethanol supernatant or polyethylene glycol supernatant) or other compositions derived from human or animal blood and characterized by the presence of coagulation factors and blood group or other undesired antibodies. Blood-derived compositions also include purified coagulation factor concentrates (e.g., Factor VIII concentrate, Factor IX concentrate, Fibrinogen concentrate) prepared by any of various methods including ion exchange, affinity, gel permeation, and/or hydrophobic chromatography or by differential precipitation.
The term "blood group" is used to identify any one of the many types into which a person's blood may be classified, based on the presence or absence of certain inherited antigens on the surface of the red blood cells. Blood of one group contains or may contain antibodies in the serum that react against the cells of other groups. These antibodies are referred to herein as "blood group antibodies" and are also referred to in the art as isoagglutinins.
There are more than thirty blood group systems, one of the most important of which is the ABO system. This system is based on the presence or absence of antigens A and B. Blood of groups A and B contain antigens A and B, respectively. Group AB contains both antigens, and group O contains neither.
The major blood group antibodies are anti-A and anti-B antibodies, which are mainly of the IgM and IgG isotypes. Blood of group A contains antibodies to antigen B. Blood of group B contains antibodies to antigen A. Blood of group AB has neither antibody, and blood of group O has both. A person whose blood contains either (or both) of the anti-A and anti-B antibodies cannot receive a transfusion of blood containing the corresponding antigens.
Specifically, when blood group antibodies are mixed with blood of an incompatible group, the antibodies coat the red blood cells of the incompatible group and cause the agglutination (clumping or sticking together) thereof. Incompatible blood group antibodies can fix complement, cause transfusion reactions and induce hemolysis, which is the destruction of red blood cells. Hemolysis can lead to anemia and other complications.
In order to avoid immunohemolysis and transfusion reactions caused by blood group antibodies in donor plasma which are incompatible with the blood group type of the blood transfusion recipient, the donor plasma and the blood group type of the recipient must be cross-matched or typed and screened.
In an effort to avoid the necessity of cross-matching and create "universal" blood-derived compositions (compositions that can be administered without regard for the blood group of donor and recipient), methods have been developed for removing blood group antibodies from blood-derived compositions. Typically, artificial antigens specific for the blood group antibody which is to be removed are attached to a support, such as a resin, which is then used to remove such antibodies. Examples of such artificial antigens can be found in U.S. Pat. Nos. 4,362,720, 4,308,376, 4,238,473, 4,195,174 and 4,137,401, all of which have been assigned to Chembiomed, Ltd. of Edmonton, Canada.
As such, commercially available resins, such as Synsorb and Chromosorb, when used with appropriate antigens, are able to remove blood group antibodies from blood-derived compositions. However, because Synsorb, Chromosorb and many other commercially available resins non-specifically adsorb coagulation factors, removal of blood group antibodies from blood-derived compositions with such resins also results in the undesired removal of an unacceptably high level of coagulation factors from such compositions.
Coagulation factors, also known as blood clotting factors, are substances present in blood that undergo a series of chemical reactions which lead to the conversion of the blood from a liquid to a solid state. Coagulation factors include Factor V, Factor VIII, Factor IX and Factor XI. Since these factors work sequentially (in a series of reactions termed a "cascade"), lack of a sufficiently high level of any one of these factors in the blood results in the inability of the blood to clot. Hence, the removal of any coagulation factors from blood-derived compositions for use in humans or animals to replace low or missing coagulation factors is not desired and is dangerous. As a result, a need has arisen to develop a method of removing blood group antibodies from blood-derived compositions so that said compositions may be "universal", without removing coagulation factors from said compositions so that blood clotting ability is not impaired.
Another problem with the resins (i.e., Synsorb and Chromosorb) currently used to remove blood group antibodies from blood-derived compositions is that such resins are only capable of completely removing blood group antibodies from such compositions at a volume ratio of 30 ml of composition per 1 ml of resin. This required ratio results in the inefficient removal of blood group antibodies. Hence, a need has also arisen to develop a more efficient method of removing blood group antibodies from blood-derived compositions without removing coagulation factors therefrom.
A still further problem connected with the removal of blood group antibodies from blood-derived compositions is that such compositions may be virus-containing. As such, any blood group antibody removal technique must also include or be compatible with virus-inactivation methods.
It is therefore an object of this invention to provide methods for removing blood group antibodies from blood-derived compositions, such that said compositions may be universal, without substantially removing coagulation factors from the compositions.
It is another object of this invention to provide methods for making blood-derived compositions from compositions which initially contained undesired antibodies and coagulation factors therein, but after treatment of such compositions with the methods of this invention, are effectively free of the undesired antibodies and have substantially retained their coagulation factors.
It is still another object of this invention to provide blood-derived compositions which, having once contained both blood group antibodies and coagulation factors, are effectively blood group antibody-free but have substantially retained their coagulation factors.
It is a further object of this invention to provide methods for making blood-derived compositions from compositions which initially contained active virus, undesired antibodies and coagulation factors therein, but after treatment of such compositions with the methods of this invention, are virus-inactivated and effectively free of the undesired antibodies, but have substantially retained their coagulation factors.
It is a still further object of this invention to provide virus-inactivated blood-derived compositions which, having once contained active virus, blood group antibodies and coagulation factors, are virus-inactivated and effectively blood group antibody-free, but have substantially retained their coagulation factors.
It is an additional object of this invention to provide a resin-antigen combination capable of removing specific undesired antibodies from blood-derived compositions while permitting the substantial retention of desired coagulation factors.
It is yet another object of this invention to provide a resin-antigen combination capable of removing blood group antibodies from blood-derived compositions while permitting the substantial retention of desired coagulation factors.